Comprehensive computational analysis of genetic and regulatory differences between individuals with African and European ancestries across four brain regions

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Project Summary / Abstract Health disparities have endured for centuries. The disparity in research for biological variations is even greater, where the explosion of genetic and environmental data has focused almost exclusively on those of European ancestry (EA). In neuroscience and genomics, individuals with recent African ancestry (AA) account for less than 5% of large-scale genomic studies but are 20% more likely to experience a major mental health crisis. To compound this issue further, studies have linked genetic differences between AA and EA for divergent responses to antipsychotics. As a result, large-scale studies for neuropsychiatric disorders have limited diagnostic accuracy for non-European ancestry individuals, hindering the development of effective equitable neurotherapeutics and potentially increasing health disparities. Despite the clear urgent need, there are no large-scale studies examining genetic or regulatory differences between AA and EA in the human brain. This proposal seeks to address this gap in research by comparing AA with well-studied EA individuals. The initial goal of this proposal is to identify genetic and regulatory difference between AA (n=784) and EA (n=678) in postmortem caudate nucleus (n=420), dentate gyrus (n=161), dorsolateral prefrontal cortex (n=434), and hippocampus (n=447), compiled from one of the largest postmortem brain collections of psychiatric disorders. This diverse large-scale postmortem brain tissue will allow us to test the hypotheses of genetic variations influence on brain region-specific transcriptional and epigenetic changes for ancestry across prenatal and postnatal life. This MOSAIC (Maximizing Opportunities for Scientific and Academic Independent Careers) Postdoctoral Career Transition Award to Promote Diversity will be supported by excellent career development resources at the Lieber Institute for Brain Development and Johns Hopkins University, and training from a mentoring team of globally recognized experts in the fields of human genetics and advanced statistical methods. It will provide a first of its kind examination of ancestry in neuroscience, which will advance our understanding of genetic variation in the human brain.